Derivatives of 3-keto steroids



United States Patent l 3,164,583 DERIVATIVES 0F 3'-KETO STEROIDS LaszloVargha, Marta Ratios, and Laszlo Szporny, Budapest, Hungary, assignorsto Richter Gedeon- Vegyszeti Gyar Rt., Budapest, Hungary 7 No Drawing.Filed Apr. 4, 1963, Ser. No. 271,554

. Claims. (Cl. 260-2395) side effects which impose importantrestrictions on their applicability.

It has surprisingly been found that the new 3-keto-A steroids of theFormula I do bH g t. m. C 1 1) where NRR stands for, a member selectedfrom the group consisting of dialkylamino, piperidino, piperazino,pyrrolidino and morpholino radicals, have a therapeutically valuableanabolic efiect without having simultaneously the undesired hormonal(e.g. androgenic or estrogenic) side eifects of the anabolic steroidsknown hitherto. These new compounds can be prepared according to thepresent invention by reacting a 3-enol-ether of the 16,l7-oxido-Apregnene-3,20-dione of the Formula II wherein A stands for a memberselected from the group consisting of alkyl, substituted alkyl, aralkyland substituted aralkyl radicals, with a basic compound of the Formula111 HNRR' (III) wherein NRR has the same meaning as above, and trans-3,164,583 Patented Jan. 5', 1965 ice forming the obtained3-alkoXy-16-(disubstituted amino)- 17a-hydroxy compound of the FormulaIV:

by hydrolysis into. the corresponding 3 keto-l6-(disubstitutedamino)-17u-hydroxy-A compound of the Formula I.

This process can be carried out by reacting a 3-al- Irony-16,17-oxido-A-pregnadiene-20-one in the presence or absence of a diluent,preferablyat elevated temperature, with the nitrogen containingbasecorresponding to the desired end product. Diluents may be chosen amongorganic solvents proving to be inert against the reaction components,such as lower alkanoles, dioxane etc. It is advantageous to use anexcess of the base used as reaction component. In case of reactioncomponents or diluents having a low' boiling point the reaction can becarried out in a closed vessel. Owing to the fact that the 16,17-0Xidoring proves to be rather resistant against bases, the reaction can beadvantageously carried out in the presence of substances having anaccelerating etfect on the reaction. According to our experience phenolor water may be advantageously used as such substances, for in theirpresence the splitting of the epoxyde ring and the simultaneous additionof the base occurs already at lower temperatures and within shortertime.

As basic compounds of the Formula III can be used for instance a dialkylamine, such as dimethyl amine or diethyl amine, further heterocyclicamines, as-morpholine, piperidine, piperazine or pyrrolidine. 4 The3-enol-ether derivatives of the Formula II obtained by the reactiondescribed above are then subjected to hydrolysis in a known manner, inthe presence of an acid, then the ether group in position 3 is split offand the corresponding 3-keto-A -steroid of Formula I, having in theD-ring a hydroxyl and a basic substituent is obtained. In the case of anacid hydrolysis the product is obtained in the form of the correspondingacid addition salt which can be transformed by alkaline treatment into afree base. 7

The compounds according to Formula II, used as starting materials, thatis the 3-enol-ethers of the 16,17-oxido- A -pregnene-3,20-dione have notbeen described in literature hitherto. These compounds can be preparedin a known manner, in the same way as the known enol ethers of other3-keto-A -steroids. Thus 'for instance the ethylenol-ether is preparedby reacting the 16,l7-oXido-A pregnene-3,20-dione with ontho formic acidethylester (see Example 1).

The compounds of the Formula I can further be preture is boiled for 2hours under reflux.

wherein NRR' has the same meaning as above, to give the correspondingS-keto-compound having the basic substituent only in the 16-position.The hydrolysis may be performed in the usual manner, by boiling thecompound to be hydrolyzed with aqueous alcohol or in the presence ofacids or bases. In the case of an acid hydrolysis the product isobtained in the form of the corresponding acid addition salt which canbe transformed by alkaline treatment into the free base. The exactconfiguration of the l6-substituent of the product obtained by the aboveprocedure could not yet be established.

The 3-enamino-Ai -steroid compounds of the Formula V, used as startingmaterials and the method of their preparation are described in ourco-pending application Serial No. 218,464 filed August 21,1962, now U.S.Patent 3,125,570.

The following examples illustrate the invention.

EXAMPLE 1 p 3-Eth0 xy-16a,17a-OxidQ-A -Pregnadiene-2O-One 2 g. of16,17-oxido-progesterone are dissolved in 80 ml. benzene; 14 ml. ortho.formic acid ethyl ester, 11 ml. abs. ethanol and as catalyst 0.8 g. of a20 percent of abs. ethanolic hydrochloric acid solution are added. Themix- After cooling the mixture is made alkaline, poured into 150 ml.Water and. the benzene phase is separated. The benzene solution iswashed With water, dried and evaporated. The residue is recrystallizedfrom abs. ethanol to which a few drops of pyridine were addedpreviously. The 3-ethoxy- 16a,17a-oxido-A -pregnadiene-20-one soobtained melts at 142-149 C.; [a] =39.7 (c.=1, chloroform).

EXAMPLE 2 16-N-M0rpholin0-1 7a-Hydr0xy-Pr0gester0ne --reflux. Aftercooling the mixture is made alkaline and hereafter shaken out threetimes with benzene.

The united benzene solution is washed with Water until neutral andevaporated to dryness. The residue is triturated with ethyl-acetate,sucked off and dried. The so obtained crystalline 3 ethoxy-A-pregnadiene-16-N-morpholinol7a-ol-20-one melts at 187-190 C.; [a]=+47.3 (c.= l, chloroform).

' EXAMPLE 3 v 16-N-Pyrr0lidin0-1 7 Ot-H ydroxy-Progesterone hydroxidesolution.

washed thoroughly with water, dried and' recrystallized A mixture of 3.5g. 16,17-oxido-progesterone-3-enolsealed tube for 16 hours.

The product is cooled, suspended in 25 ml. methanol and sucked off. The3- ethoxy A -pregnadiene-l6-N-pyrrolidino-17u-ol-20-one, recrystallizedfrom ethyl-acetate, melts at 216-221 C.; [a] =-152 (c.=1, chloroform).

A mixture of 2 g. 3-ethoxy-A-pregnadiene-16-N-pyrrolidino-17u-ol-20-one, 50 ml. ethanol and 50 ml.aqueous 2 N hydrochloric :acid is boiled for 1 hour under reflux. Aftercooling the mixture is made alkaline and hereafter shaken out threetimes with benzene. The united benzene solution is washed with Wateruntil neutral and evaporated to dryness. The residue is triturated withethyl acetate, sucked off and dried. The so obtained crystalline '16 Npyrrolidino-17ot-hydroxy-progesterone melts at EXAMPLE 4 l 6 -N-Piperidin0-1 7 Ot-H ydroxy-Progesterone A mixture of 3.5 g. of16,l7-oxido-progesterone-3-enolether, 0.9 g. phenol and 10 ml.piperidine is heated in a sealed tube for 16 hours at a temperature ofC. After cooling 25 ml. methanol is added'to the obtainedbrown oil.After stirring for a short time the solid product separates, it issucked off, washed with methanol, dried and recrystallized fromethyl-acetate.

The 3-..thoxy-A -pregnadiene-1G-N-piperidino-17a-ol-20- one so obtainedmelts at 158-163 C.; [a] =-13l (c.=1, chloroform).

A mixture of 2 g. 3-ethoxy-A -pregnadiene-16-N-piperidino-17u-ol-20-one,50 ml. ethanol and 50 ml. aqueous 2N hydrochloric acid is boiled for 1hour under reflux. After cooling the mixture is made alkaline andhereafter shaken out three times with benzene. The united benzenesolution is washed with wateruntil neutral and evaporated to dryness.The residue is triturated with ethyl-acetate, sucked off and dried. Theso obtained crystalline 16 N-piperidino-l7a-hydroxy-progesterone meltsat 157-161"; [a] =]-25 (c.=1, chloroform).

EXAMPLE 5 16-M0rph0Zin0-1 7oc-Hydroxy-Progesterone 10 g.3,16-di-(N-morpholino)-3,5-pregnadiene-l7a-ol- 20-one are dissolved in200 ml. methanol; 30 g. sodium acetate, 30 ml. water and 20 ml.-glaci-alacetic acid are added; the reaction mixture is boiled for 4 hours withstirring. V Hereafter it is cooled, filtered and finally made alkalineunder ice cooling with a 10 percent sodium The separated product issucked off,

from ethyl'acetate. The product so obtained melts at 187-190 C.; [a]'=+25 (c.=1, chloroform).

The 3,16-di-(N-morpholino) -.3,5 pregnadiene-lh-ol- 20-on'e, used asstarting material in this example and the method of its production aredescribed in our co-pending application Serial No. 218,464 mentionedabove.

In an analogous way can be obtained from the 3,16-di-(N-dimethylamino)-3,5-pregnadiene-l7a-ol-20-one, the16-dimethylamino-l7oz-hydroxy-progesterone (M.P. 129- 133 C.; [a]=I63.4, c.=l, ethanol); from the 3,16-di(N-piperidino)-3,S-pregnadiene-17a-ol-20-one the 16-N-piperidino-l7ot-hydroxy-progesterone (M.P. 157-161" C.; [a] =+25,c.=1, chloroform) and from the 3,16-di-(N-piperidino)-3,5-pregnadiene-17cx-ol-20-one the 16-N-piperidino-17a-hydroxy-progesterone (M.P. 162-165 C.; [a] =+59.5,c.=1, chloroform). All these starting materials and the methods of theirproduction are described in our co-pending application Serial No.218,468 mentioned above;

EXAMPLE 6 A mixture of 3.5 g. 16,17-oxido-progesterone-3-enolether(prepared as described in Example 1), 0.9 g. phenol and 10 g. piperazineis heated in a sealedtube for 16 hours at The produce is then cooled,suspended in 25 ml. methanol and sucked off. The 3-ethoxy-A 5 v 7 6pregnadiene-16-N-piperazino-17a-ol-20-one, recrystallized wherein NRR'represents a member selected from the from ethyl acetate melts at230237. group consisting of di-(lower a1kyl)-amino, piperidino,

Analysis.-N calculated 6.33%. N found 6.67%. piperazino, pyrrolidino andmorpholino. This product can be hydrolyzed in the same manner as 2.16-morpholino-17oc-hydroXy-progesterone.

described in the previous examples to give 16-piperazino- 5 3.16-dimethylamino-17a-hydroxy-progesterone. 17-hydroxy-progesterone. 4.16-piperidino-17ot-hydroxy-progesterone.

What we claim is: 5. 16-pyrr0lidino-17a-hydroxy-progesterone. 1. Asteroid derivative of the formula References Cited by the Examiner if 10UNITED STATES PATENTS OH 3,125,570 3/64 Vargha et a1 260239.5 p WNRR'OTHER REFERENCES 15 Diassi eta1.: J.A.C.S. 83 p. 4249-56 (1961).

Small et al.: Iour. Med. and Phar. Chem., vol. 5, pp. 962-975 (1962). 0:

LEWIS GOTTS, Primary Examiner.

1. A STEROD DERIVATIVE OF THE FORMULA